The small intestine is the primary site for the absorption of drugs administered orally. The most important element in the small intestine controlling absorption is the brush border membrane. It consists of a phospholipid bilayer into which polysaccharides and proteins are incorporated. This membrane creates absorption barriers to many polar drugs. A successful approach in the pharmaceutical industry has been to synthesize prodrugs with increasing membrane permeability by esterifying the charge functionalities. For example, the prodrug of 6-azauridine for the treatment of psoriasis and neoplastic disease is acetylated to form 2′,3′,5′-triacetyl-6-azauridine in order to enhance bioavailability (Bloch, A., “The Design of Biologically Active Nucleoside”, Drug Design, Vol. IV, Chapter 8, Ariens, E J (Ed.), Academic Press, New York, 1973) (see also, Sinkula, AA, “Application of the Prodrug Approach to Antibiotics”, Pro-drug as Novel Drug Delivery Systems, pp116–153, Higuchi, T. and Stella, V. (Eds.), ACS Symposium Series 14, American Cancer Society, Washington DC, 1975; Yalkowski, S H and Morozowich, W., Drug Design, Vol. 9, pp 121, Ariens, E J (Ed.), Academic Press, New York, 1980).
Pharmacokinetics measures the fate of drugs at the time of ingestion until elimination from the body. Bioavailability of a drug following an oral dosing is determined by its pharmacokinetics. At least three factors dictate the efficacy of a drug: 1) the degree of drug absorption through the GI tract; 2) the ease with which it becomes inactivated by the biotransformation mechanisms of the liver and 3) the rate of elimination from the body. The pharmaceutical industry usually focuses on drug formulation to increase drug efficacy by increasing drug absorption. Hence, in recent years, there has been an explosion of drug encapsulation technology. The basic premise of drug encapsulation is to improve drug delivery, lessen toxicity and improve efficacy.
The use of liposome technology as a drug delivery system has been a particularly active area of research. These lipid vesicles are generally neutral or zwitterionic lipids arranged into bilayers that entrap one (unilamellar) or more (multilamellar) spaces. In conventional liposomes, it is often difficult to entrap a high concentration of a drug. Further, in long-term storage, a drug entrapped within liposomes may leak. The cost of pharmaceutical grade phospholipids used in liposomes is also cost prohibitive. Thus, it is preferably for use in injectable formulations rather than for oral formulation (see M. Ostro, “Liposomes”, Marcel Dekker, New York, 1983).
There remains a need in the art for cost-effective methods of improving drug efficacy and bioavailability and lessening drug toxicity.